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Modeling Normal and Abnormal Trophoblasts

Award Number: R01HD094937
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Modeling Normal and Abnormal Trophoblasts - PROJECT SUMMARY Preeclampsia is a major source of maternal and fetal morbidity and mortality in pregnancy. Multiple studies have documented abnormalities in placental trophoblasts obtained from preeclamptic pregnancies at term, in development and function of both syncytiotrophoblast (STB) and extravillous trophoblast (EVTB). These cell types arise early in gestation, and it is unclear whether the abnormalities contribute to the pathophysiology of preeclampsia or are only a result of the preeclamptic environment. The proposed project will use three innovative models to address this gap in knowledge: (1) Induced pluripotent stem cells (iPSC), derived from control and preeclamptic pregnancies and differentiated to a mixed population of peri-implantation stage trophoblast by exposure to BMP4, and signaling inhibitors; (2) Induced trophoblast stem cells (TSC), obtained by conversion of the control and EOPE iPSC lines, and differentiated to the first trimester, villous stage of placental development, along either the STB or EVTB lineage; (3) 3D trophoblast organoids, derived from the TSC lines, and differentiated to predominantly STB or EVT. There are three specific aims: Aim 1 will test whether STB differentiation and, as a consequence, function, is defective in EOPE in the various models of first trimester placenta. Aim 1A will test the hypothesis that defects in STB assembly and function will be discernible in EOPE in the models of peri-implantation and villous STB developed in this laboratory, particularly under conditions of oxidative stress. In Aim 1B, single nucleus RNAseq will be used to distinguish whether TB types, especially the two previously identified clusters of 8TB, are differentially affected. Aim 2 will characterize EVTB differentiation and invasive properties in normal pregnancy and EOPE by using the TSC models. Aim 2A will determine whether defective TB invasion in EOPE is characteristic of first trimester-like EVTB, as it is in peri-implantation TB. Aim 28 will utilize organoid cultures to assess EVTB differentiation in 3-dimensional space, in homology to anchoring villi, and the role of cell-matrix interactions in acquisition of specific EVTB subtypes. Aim 3 will determine whether mitochondrial defects affect EVT and STB in EOPE Aim 3A will determine whether diminished ATP production reduces invasion in EOPE under stressful conditions. Aim 3B will test whether EOPE TBs are more susceptible to stress-induced production of reactive oxygen species. Accomplishment of these aims will uncover the mechanisms behind impaired STB and EVTB differentiation and function in patient-derived culture models of first trimester placental development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $606,194 )
2026	2026	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	9	3/19/2026	NON-COMPETING CONTINUATION	$606,194
														Subtotal = $606,194

Issue Date FY: 2025 ( Subtotal = $607,136 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	001	8	4/7/2025	NON-COMPETING CONTINUATION	$607,136
2025	2022	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	5	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $607,136

Issue Date FY: 2024 ( Subtotal = $606,395 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	001	7	5/6/2024	NON-COMPETING CONTINUATION	$55,126
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	7	5/1/2024	NON-COMPETING CONTINUATION	$551,269
														Subtotal = $606,395

Issue Date FY: 2023 ( Subtotal = $634,720 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	6	6/1/2023	COMPETING CONTINUATION	$634,720
														Subtotal = $634,720

Issue Date FY: 2022 ( Subtotal = $358,551 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	5	6/10/2022	NON-COMPETING CONTINUATION	$358,551
														Subtotal = $358,551

Issue Date FY: 2021 ( Subtotal = $358,551 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	4	6/11/2021	NON-COMPETING CONTINUATION	$358,551
														Subtotal = $358,551

Issue Date FY: 2020 ( Subtotal = $407,227 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	3	6/10/2020	NON-COMPETING CONTINUATION	$407,227
														Subtotal = $407,227

Issue Date FY: 2019 ( Subtotal = $450,099 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	2	7/17/2019	NON-COMPETING CONTINUATION	$450,099
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	002	2	8/2/2019	NON-COMPETING CONTINUATION	$0
2019	2018	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	001	1	8/2/2019	NEW	$0
														Subtotal = $450,099

Issue Date FY: 2018 ( Subtotal = $463,632 )
2018	2018	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	1	9/21/2018	NEW	$463,632
														Subtotal = $463,632

Grand Total All Awards = $4,492,505

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Modeling Normal and Abnormal Trophoblasts

Award Number: R01HD094937

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/25/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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